The long-term goal of this research is to determine how temperature and other environmental signals regulate morphology and virulence in thermally dimorphic fungi, including the fungal pathogen Histoplasma capsulatum. H. capsulatum grows in a filamentous form in the soil; once inhaled into a mammalian host, these cells switch their growth program to a parasitic yeast form that subverts the innate immune system to cause disease. Temperature is a key signal that regulates this morphogenetic switch, which is thought to be essential for H. capsulatum virulence. By elucidating how H. capsulatum cells sense and respond to host temperature, we will define critical molecular landmarks that promote changes in morphology as well as the expression of virulence traits. These studies will shed light on fundamental processes such as signal transduction and gene regulation, as well as uncover the role of temperature-dependent pathways in fungal pathogenesis. We have been studying gene circuits that control cellular differentiation in response to temperature for the pas ten years, and have made a number of major contributions to the field. We have discovered four regulatory factors that are required for yeast-phase growth in response to temperature. We have dissected the regulon of each transcription factor and discovered that they share a number of key targets that are required for morphogenesis and pathogenesis. Over the next funding period, we will focus on understanding how these regulatory factors are activated by temperature. We have implicated a histidine kinase module, including two response regulator proteins, in direct control of this transcriptional network. We will exploit these findings and our expertise in H. capsulatum molecular genetics and biochemistry to uncover molecular mechanism that link temperature to changes in morphology and virulence. Additionally, we will mine our rich and unexplored datasets of target genes to identify novel virulence factors that are induced by temperature. This work will uncover fundamental molecular properties of the yeast cell that are regulated by temperature. Ultimately our work will uncover the major molecular transitions that allow this fungus to cause disease within mammalian hosts.